The chronic inflammatory processes underlie respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. These diseases involve active inflammation in the bronchial airways, parenchyma and pulmonary vasculature of the lungs. The inflammatory process in such diseases are characterized by increased numbers of activated immune cells such as macrophages, neutrophils, eosinophils and lymphocytes and the release of a range of pro-inflammatory signaling molecules, namely cytokines and chemokines from immune and resident lung cells. The pathogenesis of these diseases is different but chronic inflammation is an underlying driving mechanism to both. COPD is strongly associated with exposure to noxious particles and gases from the external environment such as cigarette smoking and exposure to wood burning fires and is characterized by oxidative stress and an imbalance of harmful tissue proteinases with anti-proteases. These processes can lead to distinctive pathologies such as goblet metaplasia and mucus hypersecretion which cause bronchitis, alveolar wall destruction leading to emphysema and inappropriate tissue repair and smooth muscle thickening causing small airways remodeling (reviewed by Molfino & Jeffery, Pulm. Pharmacol. Ther. 2007; 20:462-72). In asthma, allergic immune mechanisms underlie the chronic inflammatory processes which contributes to airway hyperresponsiveness and structural changes in the bronchial airway, termed remodeling, such as airway smooth muscle thickening and goblet cell hyperplasia. (reviewed by Hamid & Tulic, Annu. Rev. Physiol. 2009; 71:489-507).
Bronchodilator medications that can improve lung function and improve expiratory flow are used as a standard of care for symptom relief in the treatment of respiratory diseases. Inhaled long-acting β2 adrenoceptor agonists (LABA) such as salmeterol or formoterol, or inhaled long-acting muscarinic receptor antagonists (LAMA) such as tiotropium are commonly prescribed to provide symptom relief.
Inflammation is a central process underlying many respiratory diseases and treatments that are anti-inflammatory may be efficacious and have the potential to impact disease progression. The phosphodiesterase-4 (PDE4) enzyme is a ubiquitously expressed enzyme that is responsible for catalyzing the hydrolysis of cyclic adenosine monophosphate (cAMP). Inhibition of the enzymatic activity of PDE4 with use of selective inhibitors elevates cellular levels of cAMP and this has anti-inflammatory effects in multiple immune and resident pulmonary cell types (Spina, Brit. J. Pharmacol. 2008; 155:308-15). Use of the oral PDE4 inhibitor roflumilast has demonstrated anti-inflammatory activity clinically showing a reduction of exacerbations and modest increases in lung function in COPD patients (Rabe et al., Lancet 2005; 366:563-71; Calverly et al., Am. J. Respir. Crit. Care Med. 2007; 176:154-61). Additionally, roflumilast improves lung function in severe and symptomatic patients with COPD treated with salmeterol or tiotropium but remains dose-limited due to side-effects including nausea, head-ache, diarrhea, and weight loss (Fabbri et al., Lancet 2009; 374:695-703; Calverly et al., Lancet 2009; 374:685-94). Forest Research Institute's product Daxas (roflumilast) has been approved as a once daily oral PDE4 inhibitor for the treatment of COPD. While it was accepted that Daxas demonstrated consistent evidence of efficacy concerns over a number of adverse event signals led the committee to deny approval based on the overall poor risk-to-benefit ratio. Topical delivery of a PDE4 inhibitor could therefore provide efficacious anti-inflammatory activity in the lungs whilst reducing the potential for side-effects by limiting it's exposure to the systemic circulation. Additionally, direct topical delivery may allow for higher local concentrations of the PDE4 inhibitor than could be achieved through oral dosing, and thus potential for further improvement in anti-inflammatory efficacy.
PCT Publication No. WO2005/090348 to GSK relates to compounds of formula (I) and pharmaceutically acceptable salts thereof as PDE4 Inhibitors:
wherein (inter alia):W is Ar, —CR4R5Ar or a group (y) or (y1) wherein:Ar is
y is
and y1 is
wherein A, B, D, E, and F are C—R6, N or N+—O— and R6 is inter alia H, halo, C1-6alkyl, . . . R7R8N—S(O)2—, . . . R7R8N—CO—, . . . R7R8N—, . . . CH2—NR7R8, —CH2—CH2—NR7R8, . . . —CH2—CO—NR7R8, . . .and all other variables are as defined therein.
PCT Publication No. WO2007/023110 to Hoffmann-La Roche relates to P38 Map Kinase Inhibitors of formula Ia or Ib:
wherein (inter alia):    R1 is aryl or heteroaryl;    R4 is H, C1-6alkyl, hydroxyl, amino, hetero-C1-6alkyl, hetero-C1-6alkoxy, hetero-C1-6alkylamino, heterocyclyl, heterocyclyl-C1-6alkyl, hydroxyC3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfonamido, aryl, heteroaryl, heteroaryl-C1-6alkyl, C1-6alkoxy, heteroaryl-C1-6alkoxy, —(CHRb)r—C(═O)—Rc, —(CHRb)r—O—C(═O)—Rc, —(CHRb)r—NH—C(═O)—Rc or SO2—Rc;    X and Y are N or one of X and Y is N and the other is CRd;    W is a bond, O, S(O)m, CH2, or NRf;    A is O, CH2, S(O)m, C(═O), NRh, or CH(ORh);and all other variables are as defined therein.
PCT Publication No. WO2008/015416 to Glaxo Group Limited relates to PDE4 inhibitors of formula (I):
wherein Ar is
wherein:    Q1 is NH or NMe and Q2 is C(O)—, —S(O)2—, —C(O)NH or C(O)NMe-, or    Q1 is a bond or —O— and Q2 is a bond, or    Q1 is —C(O)— and Q2 is —NH or NMe, or    Q1 is —S(O)2—, and Q2 is NH, NMe, or a bond;    L is (CH2)n or —(CH2)m—O—(CH2)m—;    R5 is H, methyl, ethyl, n-propyl, isopropyl, —CH2CH2OH, —CH2CH(Me)OH, —CH2CH2CH2OH, —CH2CH2OMe, or —CH2CH2CH2OMe; and    R6 is C1-4alkyl or C1-4alkyl substituted by on OH or OC1-3alkyl;and all other variables are as defined therein.
PCT Publication No. 2008/015437 to Glaxo Group Limited relates to PDE4 inhibitors of formula (I):
wherein:Ar is
wherein:    Q1 is NH or NMe and Q2 is —C(O)—, —S(O)2—, —C(O)NH or C(O)NMe-, or    Q1 is a bond or —O— and Q2 is a bond, or    Q1 is —C(O)— and Q2 is —NH or NMe, or    Q1 is —S(O)2—, and Q2 is NH, NMe, or a bond;    Q3 is a bond NH or NMe;    L is (CH2)n or (CH2)m—O—(CH2)m—;    R5 is H, methyl, ethyl, n-propyl, isopropyl, —CH2CH2OH, —CH2CH(Me)OH, —CH2CH2CH2OH, —CH2CH2OMe, or —CH2CH2CH2OMe; and    R6 is C1-4alkyl or C3-4alkyl substituted by on OH or OC1-3alkyl;    and all other variables are as defined therein.
PCT Publication Nos. WO2009/100166, WO2009/100167, WO2009/100169 and WO2009/0197871, all to Glaxo Group Limited relate to dual pharmacophores-PDE4-Muscarinic antagonists of the following Formulas (I):
wherein all variables are as defined in each publication.
Conventional therapeutic agents for the treatment of inflammatory respiratory conditions suffer from limited efficacy and undesired side-effect profiles. Accordingly, there remains a need in the art for new drugs designed to treat respiratory conditions including inflammatory respiratory conditions such as asthma, COPD, chronic bronchitis, bronchiectasis, cystic fibrosis, etc.